Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia.

Abstract

Understanding the complexity and dynamics of cancer cells in response to effective therapy requires hypothesis-driven, quantitative, and high-throughput measurement of genes and proteins at both spatial and temporal levels. This study was designed to gain insights into molecular networks underlying the clinical synergy between retinoic acid (RA) and arsenic trioxide (ATO) in acute promyelocytic leukemia (APL), which results in a high-quality disease-free survival in most patients after consolidation with conventional chemotherapy. We have applied an approach integrating cDNA microarray, 2D gel electrophoresis with MS, and methods of computational biology to study the effects on APL cell line NB4 treated with RA, ATO, and the combination of the two agents and collected in a time series. Numerous features were revealed that indicated the coordinated regulation of molecular networks from various aspects of granulocytic differentiation and apoptosis at the transcriptome and proteome levels. These features include an array of transcription factors and cofactors, activation of calcium signaling, stimulation of the IFN pathway, activation of the proteasome system, degradation of the PML-RARalpha oncoprotein, restoration of the nuclear body, cell-cycle arrest, and gain of apoptotic potential. Hence, this investigation has provided not only a detailed understanding of the combined therapeutic effects of RA/ATO in APL but also a road map to approach hematopoietic malignancies at the systems level.

• Authors: Pei-Zheng Zheng, Kan-Kan Wang, Qun-Ye Zhang, Qiu-Hua Huang, Yan-Zhi Du, Qing-Hua Zhang, Da-Kai Xiao, Shu-Hong Shen, Sandrine Imbeaud, Eric Eveno, Chun-Jun Zhao, Yu-Long Chen, Hui-Yong Fan, Samuel Waxman, Charles Auffray, Gang Jin, Sai-Juan Chen, Zhu Chen, Ji Zhang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 21 Pg. 7653-8 (May 24 2005) ISSN: 0027-8424 [Print] United States
• PMID: 15894607 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Arsenicals
• Oxides
• Tretinoin
• Arsenic Trioxide

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Computational Biology (methods)
• Drug Synergism
• Electrophoresis, Gel, Two-Dimensional
• Gene Expression Regulation, Neoplastic (drug effects)
• Granulocytes (cytology, drug effects)
• Humans
• Leukemia, Promyelocytic, Acute (metabolism)
• Mass Spectrometry
• Oligonucleotide Array Sequence Analysis
• Oxides (pharmacology)
• Proteomics (methods)
• Reverse Transcriptase Polymerase Chain Reaction
• Systems Biology (methods)
• Tretinoin (pharmacology)